rs886062372
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5
The NM_001082971.2(DDC):c.853C>T(p.Arg285Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,613,752 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R285Q) has been classified as Uncertain significance.
Frequency
Consequence
NM_001082971.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DDC | NM_001082971.2 | c.853C>T | p.Arg285Trp | missense_variant | 8/15 | ENST00000444124.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DDC | ENST00000444124.7 | c.853C>T | p.Arg285Trp | missense_variant | 8/15 | 1 | NM_001082971.2 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152162Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461590Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2AN XY: 727094
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152162Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74336
ClinVar
Submissions by phenotype
Deficiency of aromatic-L-amino-acid decarboxylase Pathogenic:1Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Mar 25, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 28, 2017 | The DDC c.853C>T (p.Arg285Trp) variant is a missense variant that has been reported in one study, in which it was found in a compound heterozygous state with an intron variant in two siblings with a mild aromatic l-amino acid decarboxylase deficiency phenotype (Tay et al. 2007). The p.Arg285Trp variant was absent from 100 controls and is not found in the 1000 Genomes Project, the Exome Sequencing Project, or the Exome Aggregation Consortium despite being located in a region of good sequencing coverage, suggesting it is rare. Montioli et al. (2014) demonstrated that the p.Arg285Trp variant protein was expressed at levels of 50-70% compared to wildtype and exhibited abnormal kinetics, including a reduced kcat value compared to wildtype. Based on the evidence, the p.Arg285Trp variant is classified as a variant of unknown significance but suspicious for pathogenicity for aromatic l-amino acid decarboxylase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 04, 2022 | For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Experimental studies have shown that this missense change affects DDC function (PMID: 24865461). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt DDC protein function. ClinVar contains an entry for this variant (Variation ID: 360433). This missense change has been observed in individual(s) with aromatic L-amino acid decarboxylase deficiency (PMID: 17533144). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is present in population databases (no rsID available, gnomAD 0.06%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 285 of the DDC protein (p.Arg285Trp). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at